Project Summary The prefrontal cortex (PFC) and its hippocampal and thalamic inputs play a critical role in higher order cognitive processes, including working memory. Working memory is a core cognitive process that is disrupted in a variety of psychiatric and stress-related affective disorders. Transcranial stimulation techniques have emerged as promising, non-invasive treatment option for cognitive dysfunction. However, the neurophysiological mechanisms underlying the behavioral effects of these stimulation techniques are unknown. Moreover, our current understanding of the role of neural oscillations in behavior is based on correlation and inactivation studies, and the degree to which neural oscillations mediate and exert a causal influence on cognitive function is unknown. The goal of this proposal is to address this gap using a sinusoidal optogenetic stimulation protocol to enhance neural oscillations in a pathway- and frequency-specific manner. Prior optogenetic inhibition studies demonstrate that ventral hippocampal-prefrontal gamma (30-70 Hz) synchrony is critical for encoding of spatial information into working memory, while mediodorsal thalamic-prefrontal beta (13-30 Hz) synchrony is necessary for the maintenance of information held in working memory. Aim 1 of this proposal will test the hypothesis that gamma oscillatory optogenetic stimulation of ventral hippocampal terminals in the PFC improves working memory and enhances gamma synchrony within this circuit. Aim 2 will test the hypothesis that beta oscillatory stimulation of mediodorsal terminals in the PFC improves working memory and enhances beta synchrony within this circuit. Importantly, studies of both Aims will incorporate recordings from the dorsal and ventral hippocampus, mediodorsal thalamus, and medial PFC to assess information flow through these four structures during discrete working memory task components, both in the presence and absence of oscillatory stimulation. Combined, these studies will improve our understanding of neural oscillations and determine whether they reflect causal mechanisms for information processing. Additionally, this research may lead to the development of novel protocols of frequency-specific transcranial magnetic stimulation for the treatment of cognitive dysfunction in a variety of disorders.